Lung carcinoma is one of the most common and serious types of cancer. The two main types are small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC). A vast majority (80%-85%) of cases of lung cancer are NSCLC. Epidermal growth factor receptor (EGFR) which possesses tyrosine kinase activity is mutated and/or overexpressed in many human cancers, such as NSCLC. Therefore, receptor tyrosine kinase inhibitors are useful as selective inhibitors of the growth of mammalian cancer cells.
Erlotinib is a first-line drug for treating NSCLC, and is a well-known EGFR tyrosine kinase inhibitor (EGFR-TKI), which competes with ATP for binding to the tyrosine kinase domain of the EGFR to suppress EGFR activity, to thereby block signaling in survival and proliferation of cancer cells. According to researches on lung cancer, effects of Erlotinib in patients are associated with EGFR mutations, and the efficacy of Erlotinib varies among different sensitive EGFR mutations. NSCLC patients with deletion mutations in exon 19 or leucine-to-arginine substitution at amino acid position 858 (L858R) in exon 21 are sensitive to Erlotinib treatment. In addition, Erlotinib specifically targets EGFR mutations, and is thus less harmful to normal cells.
However, it is recognized that the efficacy of Erlotinib is of limited duration about 1-2 years owing, in large part, to the emergence of drug resistance conferred by a second point mutation in the EGFR of the cancer cells. The threonine-790 to methionine (T790M) point mutation is found in approximately 50% of all NSCLC patients at the time of acquired resistance to EGFR-TKI therapy. T790M point mutation affects the ATP binding pocket of the EGFR kinase domain, resulting in inhibiting binding of EGFR and EGFR-TKI drug (Erlotinib). Furthermore, it is reported that the resistance to EGFR-TKI drug might be associated with K-RAS mutations in NSCLC patients.